Alpha aryl or heteroaryl methyl beta piperidino propanamide compounds as ORL1-receptor antagonists

Abstract

This invention provides the compounds of formula (I): or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 independently represent a hydrogen atom or the like; R 3 represents a hydrogen atom, or the like; R 4 represents a hydrogen atom or the like; represents one of the following or the like; R 5 represents an aryl group having from 6 to 10 ring atoms or the like; X represents an oxygen atom, or the like; Y represents an oxygen atom or the like and n represents an integer 0, 1 or 2. These compounds have ORL1-receptor antagonist activity; and therefore, are useful to treat diseases or conditions such as pain, various CNS diseases etc.

1. A compound of the following formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  and R 2  independently represent a hydrogen atom, a halogen atom or an alkyl group having from 1 to 3 carbon atoms; 
 R 3  represents a hydrogen atom, a cycloalkyl group having from 3 to 6 carbon atoms, a tetrahydrofuranyl group, a tetrahydropyranyl group, or an alkyl group having from 1 to 6 carbon atoms, which alkyl group is optionally substituted by 1 to 3 groups selected from a cyano group, a halogen atom, a hydroxy group, an alkoxy group having from 1 to 3 carbon atoms, an oxo group, an amino group and a mono- or di-alkylamino group having from 1 to 3 carbon atoms; 
 R 4  represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; or 
 
       
         
           
           
               
               
           
         
          represents one of the following 
       
       
         
           
           
               
               
           
         
          optionally substituted by 1 to 2 groups selected from an oxo group, a hydroxy group, a hydroxyalkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 6 carbon atoms or an alkoxyalkyl group having a total of from 2 to 6 carbon atoms; 
         R 5  represents an aryl group having from 6 to 10 ring atoms or a heteroaryl group and said heteroaryl group is a 5- to 10-membered hetero aromatic group containing from 1 to 3 hetero atoms selected from a oxygen atom, a sulfur atom and a nitrogen atom; 
         said aryl group and heteroaryl group are optionally substituted by 1 to 3 groups selected from a halogen atom, a hydroxy group, an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 6 carbon atoms interrupted by an oxygen atom, a hydroxyalkyl group having from 1 to 3 carbon atoms, an amino group, a mono- or di-alkylamino group having from 1 to 3 carbon atoms, an aminocarbonyl group, a mono- or di-alkylaminocarbonyl group having from 1 to 3 carbon atoms in each alkyl group, an alkanoylamino group having from 1 to 3 carbon atoms and an alkylsulfonylamino group having from 1 to 3 carbon atoms; 
         R 6  represents a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms, an alkanoyl group having from 1 to 3 carbon atoms or an alkylsulfonyl group having from 1 to 3 carbon atoms; 
         —X—Y— represents a group of the formula —N(R 7 )C(═O)—, —C(═O)N(R 7 )—, —N(R 7 )CH 2 —, —CH 2 N(R 7 )—, —N(R 7 )SO 2 —, —SO 2 N(R 7 )—, —CH 2 CH 2 —, —CH═CH—, —CH(CH 2 OH)CH 2 —, —CH 2 CH(CH 2 OH)—, —CH 2 CH(OH)—, —CH(OH)CH 2 —, —C(R 7 )(R 8 )—O— or —O—C(R 7 )(R 8 )— 
          R 7  represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R 8  represents a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms or a hydroxyalkyl group having from 1 to 3 carbon atoms; 
         n represents an integer 0, 1 or 2. 
       
     
     
       2. A compound according to  claim 1 , wherein R 1  and R 2  independently represent a hydrogen atom or a fluorine atom. 
     
     
       3. A compound according to  claim 1  wherein,
 R 3  represents a hydrogen atom, a tetrahydrofuranyl group, an alkyl group having from 1 to 6 carbon atoms optionally substituted by 1 to 3 groups selected from a cyano group, a halogen atom, a hydroxy group, an alkoxy group having from 1 to 3 carbon atoms, an oxo group and a di-alkylamino group having from 1 to 3 carbon atoms; and 
 R 4  represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; or 
 
       
         
           
           
               
               
           
         
          represents one of the following 
       
       
         
           
           
               
               
           
         
       
       optionally substituted by 1 to 2 groups selected from a hydroxy group, a hydroxyalkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 3 carbon atoms or an alkoxyalkyl group having a total of from 2 or 3 carbon atoms. 
     
     
       4. A compound according to  claim 1 , R 3  represents a hydrogen atom, a tetrahydrofuranyl group, an alkyl group having from 1 to 6 carbon atoms optionally substituted by 1 substituent selected from a cyano group, a trifluoromethyl group, a hydroxy group, a methoxy group, an oxo group and a dimethylamino group; and
 R 4  represents a hydrogen atom or a methyl group; or 
 
       
         
           
           
               
               
           
         
          represents one of the following 
       
       
         
           
           
               
               
           
         
       
       optionally substituted by 1 to 2 groups selected from a hydroxy group, a hydroxymethyl group, a methoxy group, a methyl group and a methoxymethyl group. 
     
     
       5. A compound according to  claim 1  wherein
 R 3  represents a hydrogen atom, a tetrahydrofuranyl group, a methyl group, an hydroxyethyl group, a methoxybutyl group, a hydroxybutyl group, a methoxyethyl group, a hydroxypentyl group, a hydroxypropyl group, a cyano methyl group, a cyanomethyl group, a dimethylaminobutyl group, a trifluoroethyl group or a dimethylaminoethyl group; and 
 R 4  represents a hydrogen atom or a methyl group; or 
 
       
         
           
           
               
               
           
         
          represents one of the following 
       
       
         
           
           
               
               
           
         
       
     
     
       6. A compound according to  claim 1  wherein
 R 5  represents a phenyl group or a heteroaryl group and said heteroaryl group is a 5- to 6-membered hetero aromatic group containing from 1 to 2 nitrogen heteroatoms or 1 or 2 nitrogen heteroatoms and 1 oxygen or 1 sulfur atom; 
 said phenyl group and heteroaryl group are optionally substituted by 1 to 3 groups selected from a halogen atom, a hydroxyl group, an alkyl group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 6 carbon atoms interrupted by an oxygen atom, a hydroxyalkyl group having from 1 to 3 carbon atoms, an amino group and an alkylsulfonylamino group having from 1 to 3 carbon atoms. 
 
     
     
       7. A compound according to  claim 1  wherein
 R 5  represents a phenyl group or a heteroaryl group selected from a pyridyl group, a thiazolyl group, a pyrazolyl group and an oxazolyl group; 
 said phenyl group is optionally substituted by 1 to 3 groups selected from a fluorine atom, a chlorine atom, a hydroxy group, a methyl group, a methoxymethyl group, a hydroxymethyl group, an amino group and methanesulfonylamino. 
 
     
     
       8. A compound according to  claim 1  wherein
 —X—Y— represents a group of the formula —N(CH 3 )C(═O)—, —N(CH 3 )CH 2 —, —N(CH 3 )SO 2 —, —CH 2 O—, —CH(CH 3 )O—, C(CH 3 ) 2 O—, —CH(CH 2 OH)O—, —CH 2 CH 2 —, —CH(CH 2 OH)CH 2 —, —CH(OH)CH 2 —, —CH═CH—, or —CH 2 CH(OH)—. 
 
     
     
       9. A compound according to any one of  claims 1  to  8 , wherein
 —X—Y— represents a group of the formula —N(CH 3 )C(═O)—, —CH 2 O—, —CH(CH 3 )O—, C(CH 3 ) 2 O— or —CH 2 CH 2 —. 
 
     
     
       10. A compound according to  claim 1  wherein
 n represents an integer 0. 
 
     
     
       11. A compound according to  claim 1  selected from:
 3-(2,3-Dihydro-1′H-spiro[indene-1,4′-piperidin]-1′-yl)-N,N-dimethyl-2-(pyridin-2-ylmethyl)propanamide; 
 N,N-Dimethyl-3-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2-(1,3-thiazol-4-ylmethyl)propanamide; 
 3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N,N-dimethyl-2-(pyridin-2-ylmethyl)propanamide; 
 (−)-3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N,N-dimethyl-2-(pyridin-2-ylmethyl)propanamide; 
 3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N-(2-hydroxyethyl)-N-methyl-2-(pyridin-2-ylmethyl)propanamide; 
 3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N-(2-methoxyethyl)-N-methyl-2-(pyridin-2-ylmethyl)propanamide; 
 3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N,N-dimethyl-2-(1,3-thiazol-4-ylmethyl)propanamide; 
 (−)-3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N,N-dimethyl-2-(1,3-thiazol-4-ylmethyl)propanamide; 
 3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N-(2-methoxyethyl)-N-methyl-2-(1,3-thiazol-4-ylmethyl)propanamide; 
 3-(5-Fluoro-1-methyl-2-oxo-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)-N,N-dimethyl-2-(pyridin-2-ylmethyl)propanamide; 
 3-(3,3-Dimethyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N,N-dimethyl-2-(pyridin-2-ylmethyl)propanamide; 
 1-[3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2-(1,3-thiazol-4-ylmethyl)propanoyl]-3-methylazetidin-3-ol; 
 N,N-Dimethyl-3-(3-methyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2-(pyridin-2-ylmethyl)propanamide; 
 3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N,N-dimethyl-2-(1H-pyrazol-1-ylmethyl)propanamide; 
 (−)-3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N,N-dimethyl-2-(1H-pyrazol-1-ylmethyl)propanamide; 
 3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N-(2-hydroxyethyl)-N-methyl-2-(1,3-thiazol-4-ylmethyl)propanamide; 
 (−)-3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N-(2-hydroxyethyl)-N-methyl-2-(1,3-thiazol-4-ylmethyl)propanamide; 
 3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N-(2-methoxy-2-methylpropyl)-N-methyl-2-(1,3-thiazol-4-ylmethyl)propanamide; 
 1-[3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2-(1,3-thiazol-4-ylmethyl)propanoyl]-3-methylpyrrolidin-3-ol; 
 3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N-(3-hydroxy-3-methylbutyl)-N-methyl-2-(1,3-thiazol-4-ylmethyl)propanamide; 
 3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N-methyl-N-(tetrahydrofuran-3-yl)-2-(1,3-thiazol-4-ylmethyl)propanamide; 
 N,N-Dimethyl-3-(3-methyl-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-2-(1,3-thiazol-4-ylmethyl)propanamide; 
 1′-[3-Azetidin-1-yl-3-oxo-2-(1,3-thiazol-4-ylmethyl)propyl]-6-fluoro-3H-spiro[2-benzofuran-1,4′-piperidine]; 
 3-(6-Fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)-N,N-dimethyl-2-[(4-methyl-1H-pyrazol-1-yl)methyl]propanamide; 
 3-(4-Chloro-1H-pyrazol-1-yl)-2-[(6-fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)methyl]-N,N-dimethylpropanamide; 
 (−)-3-(4-Chloro-1H-pyrazol-1-yl)-2-[(6-fluoro-1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)methyl]-N,N-dimethylpropanamide; 
 3-(6-Fluoro-3,4-dihydro-1′H-spiro[isochromene-1,4′-piperidin]-1′-yl)-N,N-dimethyl-2-(1H-pyrazol-1-ylmethyl)propanamide; 
 3-(6-Fluoro-3,4-dihydro-1′H-spiro[isochromene-1,4′-piperidin]-1′-yl)-N,N-dimethyl-2-(1,3-thiazol-4-ylmethyl)propanamide; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       12. A pharmaceutical composition including a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in  claim 1  together with a pharmaceutically acceptable excipient.